Significance: Although osteocytes make up over 90% of all bone cells, little is known about their function, compared to other bone cells, the osteoblast and the osteoclast. The osteocyte is the cell ideally situated in bone to sense mechanical strain and translate that strain into signals for bone formation and bone resorption. However, the role of osteocytes in modulating strain effects on bone modeling and remodeling is unclear: Approach: This Program Project Application was initiated to develop a time approach to clarify the mechanisms by which osteocytes sense and respond to mechanical strain in a manner that results in either bone loss, remodeling, or pathologic repair. The focus of this application is to determine the role of the osteocyte in signaling bone resorption. The mechanisms whereby osteocytes translate mechanical strain into signals include intracellular and extracellular signaling initiate or controlling osteoblast/osteoclast activity and the expression of genes necessary and specific for osteocyte function. The specific aims of the program project are: 1) determine the role and regulation of gap junction function in osteocytes, 2) to determine the levels of mechanical strains sensed by the osteocyte resulting from the mechanical stimulation of bone, 3) to identify osteocyte specific genes and their regulation by mechanical strain and 4) to determine the role of the osteocyte in osteoclast formation. Innovation: Novel approaches to answer these questions include the use of an osteocyte-like cell line, the use of bioengineering micro- mechanisms techniques to measure strain sensed by individual osteocytes, fluorescence image analysis to examine gene expression in single cells, novel animal models, and gene array technology to examine genes regulated by mechanical strain. Investigators and Environment: The program project is composed of investigators with specific talents, training and expertise in the areas of molecular biology, cell known for its contributions in the area of bone and cartilage biology. Knowledge gained will lead to identification of ways to regulate or inhibit the osteocytic signals of resorption that can be used towards the prevention and treatment of bone loss due to immobilization, space flight, microdamage, aging and disease states such as osteoporosis.